Abstract: BACKGROUND: Soft tissue sarcomas (STS) are a highly heterogeneous group of rare malignant solid tumors. Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise all STS except rhabdomyosarcoma. In patients with advanced local or metastatic disease, autologous hematopoietic stem cell transplantation (HSCT) applied after high-dose chemotherapy (HDCT) is a planned rescue therapy for HDCT-related severe hematologic toxicity.
OBJECTIVES: To assess the effectiveness and safety of HDCT followed by autologous HSCT for all stages of soft tissue sarcomas in children and adults.
SEARCH STRATEGY: We searched the electronic databases CENTRAL (The Cochrane Library 2010, Issue 2), MEDLINE and EMBASE (February 2010). Online trial registers, congress abstracts and reference lists of reviews were searched and expert panels and authors were contacted.
SELECTION CRITERIA: Terms representing STS and autologous HSCT were required in the title, abstract or keywords. In studies with aggregated data, participants with NRSTS and autologous HSCT had to constitute at least 80% of the data. Comparative non-randomized studies were included because randomized controlled trials (RCTs) were not expected. Case series and case reports were considered for an additional descriptive analysis.
DATA COLLECTION AND ANALYSIS: Study data were recorded by two review authors independently. For studies with no comparator group, we synthesised results for studies reporting aggregate data and conducted a pooled analysis of individual participant data using the Kaplan-Meyer method. The primary outcomes were overall survival (OS) and treatment-related mortality (TRM).
MAIN RESULTS: We included 54 studies, from 467 full texts articles screened (11.5%), reporting on 177 participants that received HSCT and 69 participants that received standard care. Only one study reported comparative data. In the one comparative study, OS at two years after HSCT was estimated as statistically significantly higher (62.3%) compared with participants that received standard care (23.2%). In a single-arm study, the OS two years after HSCT was reported as 20%. In a pooled analysis of the individual data of 54 participants, OS at two years was estimated as 49% (95% CI 34% to 64%). Data on TRM, secondary neoplasia and severe toxicity grade 3 to 4 after transplantation were sparse. All 54 studies had a high risk of bias.
AUTHORS' CONCLUSIONS: Due to a lack of comparative studies, it is unclear whether participants with NRSTS have improved survival from autologous HSCT following HDCT. Owing to this current gap in knowledge, at present HDCT and autologous HSCT for NRSTS should only be used within controlled trials.
Abstract: Introduction
Acquired severe aplastic anemia (SAA) is a rare and progressive disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells is a first-line treatment option if HLA-matched related donors are available. First-line immunosuppressive therapy may be offered as alternative. The aim was to compare the outcome of these patients in controlled trials.
Methods
A systematic search was performed in the bibliographic databases MEDLINE, EMBASE, and The Cochrane Library. To show an overview of various outcomes by treatment group we conducted a meta-analysis on overall survival. We evaluated whether studies reported statistically significant factors for improved survival.
Results
26 non-randomized controlled trials (7,955 patients enrolled from 1970 to 2001) were identified. We did not identify any RCTs. Risk of bias was high except in 4 studies. Young age and recent year of treatment were identified as factors for improved survival in the HSCT group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the IST group. In 19 studies (4,855 patients), summary statistics were sufficient to be included in meta-analysis. Considerable heterogeneity did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies.
Conclusions
Young age and recent year of treatment were identified as factors for improved survival in the transplant group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the immunosuppressive group. Considerable heterogeneity of non-randomized controlled studies did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies.
Abstract: Acquired severe aplastic anemia is a rare disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells from unrelated donors is a treatment option frequently offered to patients after failed immunosuppressive therapy. The aim was to investigate the outcome of these patients treated with unrelated donor transplants. Systematic literature searches were performed in MEDLINE, EMBASE, and The Cochrane Library. All databases were searched from inception to June 2009. Only full-text publications and studies including at least 10 patients were considered. The primary outcome was 5-year overall survival from the day of transplantation and the secondary outcomes were graft failure and graft-versus-host disease. A meta-analysis of survival estimates was conducted and heterogeneity was investigated. A total of 18 studies, one controlled trial and 17 case series were identified. The overall survival at five years and the corresponding confidence interval was stated in 8 studies and ranged from 28% to 94%. A meta-analysis revealed considerable heterogeneity between the studies that could not be explained and was also present in subgroups of the studies. The proportion of acute graft failure was 45% in one study using only umbilical cord blood, and it was reported to be 0-26% in 15 studies using mainly bone marrow as stem cell source after different follow-up periods. Acute GVHD grade II-IV was reported for 8-86% and extensive chronic GVHD for 0-38% of the evaluated patients in 16 studies. Recipient age, human leukocyte antigen match, performance status, year of transplantation, and conditioning with serotherapy were identified as significant factors for improved survival. Unrelated donor hematopoietic stem cell transplantation in patients with acquired severe aplastic anemia after failure to immunosuppressive therapy is a treatment option. A stable physical condition of the patients before receiving the transplant (for example, performance and age) may be associated with a better survival. Detailed HLA-matching facilitated by DNA-based typing, among other factors, may have contributed to recent improvements on survival after unrelated donor HSCT as a second-line treatment.
Abstract: BACKGROUND: Primary study selection between systematic reviews is inconsistent, and reviews on the same topic may reach different conclusions. Our main objective was to compare systematic reviews on negative pressure wound therapy (NPWT) regarding their agreement in primary study selection.
METHODS: This retrospective analysis was conducted within the framework of a systematic review (a full review and a subsequent rapid report) on NPWT prepared by the Institute for Quality and Efficiency in Health Care (IQWiG). For the IQWiG review and rapid report, 4 bibliographic databases (MEDLINE, EMBASE, The Cochrane Library, and CINAHL) were searched to identify systematic reviews and primary studies on NPWT versus conventional wound therapy in patients with acute or chronic wounds. All databases were searched from inception to December 2006. For the present analysis, reviews on NPWT were classified as eligible systematic reviews if multiple sources were systematically searched and the search strategy was documented. To ensure comparability between reviews, only reviews published in or after December 2004 and only studies published before June 2004 were considered. Eligible reviews were compared in respect of the methodology applied and the selection of primary studies.
RESULTS: A total of 5 systematic reviews (including the IQWiG review) and 16 primary studies were analysed. The reviews included between 4 and 13 primary studies published before June 2004. Two reviews considered only randomised controlled trials (RCTs). Three reviews considered both RCTs and non-RCTs. The overall agreement in study selection between reviews was 96% for RCTs (24 of 25 options) and 57% for non-RCTs (12 of 21 options). Due to considerable disagreement in the citation and selection of non-RCTs, we contacted the review authors for clarification (this was not initially planned); all authors or institutions responded. According to published information and the additional information provided, most differences between reviews arose from variations in inclusion criteria or inter-author study classification, as well as from different reporting styles (citation or non-citation) for excluded studies.
CONCLUSION: The citation and selection of primary studies differ between systematic reviews on NPWT, particularly with regard to non-RCTs. Uniform methodological and reporting standards need to be applied to ensure comparability between reviews as well as the validity of their conclusions.
Abstract: OBJECTIVE: To systematically examine the clinical effectiveness and safety of negative pressure wound therapy (NPWT) compared with conventional wound therapy.
DATA SOURCES: MEDLINE, EMBASE, CINAHL, and the Cochrane Library were searched. Manufacturers were contacted, and trial registries were screened.
STUDY SELECTION: Randomized controlled trials (RCTs) and non-RCTs comparing NPWT and conventional therapy for acute or chronic wounds were included in this review. The main outcomes of interest were wound-healing variables. After screening 255 full-text articles, 17 studies remained. In addition, 19 unpublished trials were found, of which 5 had been prematurely terminated.
DATA EXTRACTION: Two reviewers independently extracted data and assessed methodologic quality in a standardized manner.
DATA SYNTHESIS: Seven RCTs (n = 324) and 10 non-RCTs (n = 278) met the inclusion criteria. The overall methodologic quality of the trials was poor. Significant differences in favor of NPWT for time to wound closure or incidence of wound closure were shown in 2 of 5 RCTs and 2 of 4 non-RCTs. A meta-analysis of changes in wound size that included 4 RCTs and 2 non-RCTs favored NPWT (standardized mean difference: RCTs, -0.57; non-RCTs, -1.30).
CONCLUSIONS: Although there is some indication that NPWT may improve wound healing, the body of evidence available is insufficient to clearly prove an additional clinical benefit of NPWT. The large number of prematurely terminated and unpublished trials is reason for concern.
Abstract: BACKGROUND: Negative pressure wound therapy (NPWT) is widely applied, although the evidence base is weak. Previous reviews on medical interventions have shown that conclusions based on published data alone may no longer hold after consideration of unpublished data. The main objective of this study was to identify unpublished randomised controlled trials (RCTs) on NPWT within the framework of a systematic review.
METHODS: RCTs comparing NPWT with conventional wound therapy were identified using MEDLINE, EMBASE, CINAHL and The Cochrane Library. Every database was searched from inception to May 2005. The search was updated in December 2006. Reference lists of original articles and systematic reviews, as well as congress proceedings and online trial registers, were screened for clues to unpublished RCTs. Manufacturers of NPWT devices and authors of conference abstracts were contacted and asked to provide study information. Trials were considered nonrandomised if concealment of allocation to treatment groups was classified as "inadequate". The study status was classified as "completed", "discontinued", "ongoing" or "unclear". The publication status of completed or discontinued RCTs was classified as "published" if a full-text paper on final study results (completed trials) or interim results (discontinued trials) was available, and "unpublished" if this was not the case. The type of sponsorship was also noted for all trials.
RESULTS: A total of 28 RCTs referring to at least 2755 planned or analysed patients met the inclusion criteria: 13 RCTs had been completed, 6 had been discontinued, 6 were ongoing, and the status of 3 RCTs was unclear. Full-text papers were available on 30% of patients in the 19 completed or discontinued RCTs (495 analysed patients in 10 published RCTs vs. 1154 planned patients in 9 unpublished RCTs). Most information about conference abstracts and unpublished study information referring to trials that were unpublished at the time these documents were generated was obtained from the manufacturer Kinetic Concepts Inc. (KCI) (19 RCTs), followed by The Cochrane Library (18) and a systematic review (15). We were able to obtain some information on the methods of unpublished RCTs, but results data were either not available or requests for results data were not answered; the results of unpublished RCTs could therefore not be considered in the review. One manufacturer, KCI, sponsored the majority of RCTs (19/28; 68%). The sponsorship of the remaining trials was unclear.
CONCLUSION: Multi-source comprehensive searches identify unpublished RCTs. However, lack of access to unpublished study results data raises doubts about the completeness of the evidence base on NPWT.
Abstract: Five neonates who suffered from an unexpected long period of respiratory failure, muscular hypotonia, and drowsiness were observed in a retrospective study. Prior to this general depression, unusually high doses of diazepam were administered to all patients via intravenous bolus injection. Serum levels of diazepam and its active metabolites were substantially elevated in the course of the disease. The persistence of the very long-acting N-desmethyldiazepam with considerable extension in neonates and even more exaggerated in premature infants is emphasized due to the reduced capacity of the hepatic biotransformation system. CONCLUSION: The intravenous application of diazepam imposes a risk of marked and prolonged general depression in neonates. Pronounced adverse effects are to be expected for prematures even after a single diazepam intravenous bolus if the dosage is not appropriate. Diazepam should not be used for short sedation and is not the drug of choice for anticonvulsant therapy in neonates.
Abstract: Of a total of 117 bone marrow transplant (BMT) recipients in the period from August 1988 to November 1995, 9 (7.7%) developed haemorrhagic cystitis. This condition was characterized in all nine patients by late onset (day +24 to +50 post-BMT), long duration (1 to 7 weeks), and the excretion of BK virus in the urine, as confirmed by electron microscopy, DNA hybridization and PCR analysis. Adenovirus was not involved. The serological assessment of BK virus-specific IgM and IgG pre- and post-BMT is consistent with viral reactivation in all patients, although a primary infection cannot be absolutely excluded in a single patient. A significant correlation between the use of high-dose busulphan (16 mg/kg) in the preparative regimen and development of haemorrhagic cystitis (P = 0. 0003) was evident. The severe course of the disease in two patients resulted in bladder tamponade; bleeding could not be inhibited with coagulation and laser treatment. Deterioration was prevented by bladder irrigation via a suprapubic catheter. Remission occurred spontaneously in all patients. CONCLUSION: BK virus induced haemorrhagic cystitis in a paediatric bone marrow transplantation recipients is characterized by late onset, long duration, viral reactivation and correlates to high-dose busulphan. Severe bleeding could not be influenced by surgical intervention.
Abstract: Hemorrhagic cystitis (HC) is a major complication of bone marrow transplantation (BMT). We describe the clinical course and urological management of BK polyomavirus-associated HC in children after bone marrow transplantation. From 8/88 to 11/95, a total of 117 consecutive pediatric patients received BMT. Nine patients (7. 7%) developed HC after transplantation. HC in all 9 patients was characterized by late onset (day +24 to +50 post-BMT), long duration (1-7 weeks) and the excretion of BK polyomavirus in the urine as confirmed by electron microscopy, DNA hybridization and PCR techniques. Six children developed mild HC (grade 1-2) and were treated successfully by hyperhydration. In 3 patients, severe HC (grade 3-4) over 6 weeks required surgical interventions. In these 3 patients, cystoscopy revealed circumscript papulous tumors as the source of hematuria. Severe and persistent hematuria required blood transfusions, insertion of large suprapubic catheters and permanent bladder irrigation because of recurrent blood clot retention. Attempts to stop the hematuria in 2 of these patients by coagulation and laser vaporization (Nd:YAG) failed to stop the bleeding. Differential diagnosis of hematuria after BMT includes urinary tract infection, cyclophosphamide-induced chemical cystitis and bleeding due to BMT-induced thrombocytopenia. With the increasing number of BMTs in children, urologists may be confronted with BK polyomavirus-associated HC and must consider this in the differential diagnosis of hematuria after BMT.
Abstract: Components of the mitochondrial branched chain alpha-ketoacid dehydrogenase multienzyme complex are all encoded by nuclear genes. The functional complex is formed with a known stoichiometric relationship of subunits, but how they enter the mitochondria and form the complex is not defined. Although cytosolic precursors for several of the proteins have been identified, the requirements for import and processing have not been described. Here we demonstrate the similar requirements for in vitro import and processing of the three catalytic subunits unique the this complex. Import was not affected by the amount of endogenous BCKD within the mitochondria. No cooperativity or competition among the subunits for import was found when subunits were used in combination. The relative rates of entry are E1alpha>E2>/=E1beta, making E1beta the limiting component supporting previously reported observations.
Abstract: Maple syrup urine disease results from defects in the branched chain alpha-ketoacid dehydrogenase complex. Cells from seven German, three Turkish, and two Italian families including five consanguineous matings were analyzed for the causative mutations. Enzyme assays were used to confirm the initial clinical diagnosis of all probands. Immunoblots of mitochondrial proteins from these probands revealed reduced expression of the E1 alpha and beta proteins of the complex. Previous studies showed that interaction of alpha and beta was necessary to stabilize both proteins so that defects in either protein can result in decreased presence of both. The E1 alpha Y393N mutation common in the Mennonite population that results in diminished amounts of both alpha and beta proteins was not the cause of the reduction in these European patients.
Abstract: We describe the application of deletion screening by amplification of deletion-prone exons via polymerase chain reaction (PCR) in a family with a sporadic case of Duchenne muscular dystrophy (DMD). No DNA was available from the affected patient who died 12 years beforehand at the age of 18 years. Material obtained prenatally from two male fetuses exhibited an identical deletion. These findings effectively transformed a sporadic case into a familial case and a numerical carrier risk was substituted by obligate carrier status. Additionally an indirect genotype analysis was replaced by the possibility of direct DNA analysis. Genetic counselling, formerly based upon incomplete data, can now be aided by precise risk assessment.
Abstract: pJU78 is a 2.9-kb cloned human DNA segment derived from Xq24-q26. When used as a hybridization probe, it detects some 25 related sequences dispersed over the genome, including several autosomes and the X and Y chromosomes. Several pJU78-related sequences were chromosomally allocated and five different restriction fragment length polymorphisms detected and partially characterized in population and family studies. This sequence family was not found in non-primate species. The sequence appears to lack CpG-island character and is not detectably expressed in a variety of human tissues.
Abstract: Principles of genetic disease analysis using molecular genetic techniques are illustrated. Direct and indirect genotyping is described with cystic fibrosis as an example. The possibilities to combine genetic markers for "full informativity" are included.
Abstract: The F508 deletion in the cystic fibrosis transmembrane conductance regulator (CFTR) gene was found in 8 out of 30 Turkish cystic fibrosis (CF) chromosomes (27%). Five Turkish delta F508 CF chromosomes were associated with the risk haplotype B in KM19 (2 allele)/XV2c (1 allele). In the Turkish population, cystic fibrosis is predominantly caused by mutations other than the F508 deletion.
Notes: Programm der 9. Deutschen Konferenz für Tabakkontrolle:
http://www.dkfz.de/de/tabakkontrolle/download/Deutsche_Konferenzen_fuer_Tabakkontrolle/9_Deutsche_Konferenz_fuer_Tabakkontrolle/Programm_9_Deutsche_Konferenz_fuer_Tabakkontrolle.pdf
WHO-Kollaborationszentrum für Tabakkontrolle der Stabsstelle Krebsprävention des DKFZ:
http://www.dkfz.de/de/tabakkontrolle/
Abstract: Many men will eventually develop prostate cancer with increasing age that remains silent (indolent, does not become clinically significant). Low-risk prostate cancer is a slow growing tumor in many affected men and stays localized within the prostate gland for many years without symptoms. Some tumors grow and threaten a patient's life.
Localized prostate cancer is characterized by confinement to the prostate gland and an intact capsule combined with an absence of both regional lymph node metastasis and distant metastasis. The patient may choose from 4 different treatment concepts that are recommended by the European Association of Urology for the corresponding stages of prostate cancer: Radical prostatectomy (RP), external-beam radiotherapy (EBRT), no primary therapy (NPT) such as active surveillance, and permanent interstitial low-dose-rate brachytherapy (LDR-BT), a short-distance radiation therapy in which low-energy radioactive sources are implanted permanently into the prostate. The aim of this systematic review was to assess the benefit and harm of LDR-BT relative to RP, EBRT, or NPT in men with localized prostate cancer.
A total of 31 studies, including 1 randomized controlled trial, were identified. Risk of bias was high for all 31 studies. The current evidence does not allow a determination of whether LDR-BT has an additional benefit or harm compared to other treatment alternatives in patients with localized prostate cancer. We found a low amount of evidence in studies that exclusively compared LDR-BT with other treatment modalities. LDR-BT may have some different physician-reported severe adverse events: Urogenital late toxicity grade 2 to 3 was more common in the LDR-BT group when compared to the EBRT group. LDR-BT may have some different patient-reported outcomes: Better scores for sexual and urinary function as well as urinary incontinence were reported for LDR-BT compared to RP; better scores for bowel function were reported for LDR-BT compared to EBRT. Biochemical (prostate-specific antigen) recurrence-free survival is the most commonly used end point in the included studies and may be the best tool available for detecting recurrence of prostate cancer in individuals. However, for the purpose of statistical comparison of different treatments, it is not an appropriate end point.
The current evidence is insufficient to allow a definitive conclusion about overall survival. Randomized trials focusing on long-term survival are needed to clarify the relevance of LDR-BT in patients with localized prostate cancer. Ethical issues such as patient and physician preferences as well as transparent counseling should be considered in designs of future studies. We have identified 3 ongoing randomized controlled trials that may provide sufficient evidence in upcoming years to allow conclusions about the comparative effectiveness of LDR-BT: Name of study, Country (status as of 09 January 2012); PREFERE, Germany (Start in 2012); SABRE 1, UK, Canada (Ongoing); START, Canada, USA, UK.
